@article{0ca8901096244027a53e0832cb5082ed,
title = "Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors",
abstract = "Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapeutics for many diseases, including cancer, in clinical trials. One PARP inhibitor, olaparib (Lynparza, AstraZeneca), was recently approved by the FDA to treat ovarian cancer with mutations in BRCA genes. BRCA1 and BRCA2 have essential roles in repairing DNA double-strand breaks, and a deficiency of BRCA proteins sensitizes cancer cells to PARP inhibition. Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907). PARP1 pY907 increases PARP1 enzymatic activity and reduces binding to a PARP inhibitor, thereby rendering cancer cells resistant to PARP inhibition. The combination of c-Met and PARP1 inhibitors synergized to suppress the growth of breast cancer cells in vitro and xenograft tumor models, and we observed similar synergistic effects in a lung cancer xenograft tumor model. These results suggest that the abundance of PARP1 pY907 may predict tumor resistance to PARP inhibitors, and that treatment with a combination of c-Met and PARP inhibitors may benefit patients whose tumors show high c-Met expression and who do not respond to PARP inhibition alone.",
author = "Yi Du and Hirohito Yamaguchi and Yongkun Wei and Hsu, {Jennifer L.} and Wang, {Hung Ling} and Hsu, {Yi Hsin} and Lin, {Wan Chi} and Yu, {Wen Hsuan} and Leonard, {Paul G.} and Lee, {Gilbert R.} and Chen, {Mei Kuang} and Katsuya Nakai and Hsu, {Ming Chuan} and Chen, {Chun Te} and Ye Sun and Yun Wu and Chang, {Wei Chao} and Huang, {Wen Chien} and Liu, {Chien Liang} and Chang, {Yuan Ching} and Chen, {Chung Hsuan} and Morag Park and Philip Jones and Hortobagyi, {Gabriel N.} and Hung, {Mien Chie}",
note = "Funding Information: This study was funded in part by the following: the US National Institutes of Health grants (nos. CA109311 (M.-C. Hung) and CA099031 (M.-C. Hung), and a Cancer Center Support Grant CA16672); the Susan G. Komen Foundation (SAC100016 (M.-C. Hung)); the Breast Cancer Research Foundation; the Patel Memorial Breast Cancer Endowment Fund; The University of Texas MD Anderson–China Medical University and Hospital Sister Institution Fund; the Ministry of Science and Technology, International Research-intensive Centers of Excellence in Taiwan (I-RiCE; MOST 104-2911-I-002-302 (M.-C. Hung)); the Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence (MOHW104-TDU-B-212-124-002 (M.-C. Hung)); the Center for Biological Pathways at The University of Texas MD Anderson Cancer Center; and the Ting Tsung and Wei Fong Chao Research Fund. We also thank S. Patterson of the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for her editorial assistance. Publisher Copyright: {\textcopyright} 2016 Nature America, Inc. All rights reserved.",
year = "2016",
month = feb,
day = "1",
doi = "10.1038/nm.4032",
language = "English (US)",
volume = "22",
pages = "194--201",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "2",
}